Gene-Environment Interactions Between Per- and Polyfluoroalkyl Substances (PFAS) and Folate-Related SNPs on Birth Weight and Head Circumference: Findings from the Taiwan Birth Panel Study

Background Folate metabolism is crucial for fetal development, while per- and polyfluoroalkyl substances (PFAS) are associated with adverse birth outcomes and lower folate levels. However, no study tested the interaction between PFAS exposure and genetic variations in the folate pathway on birth outcomes. The study investigated whether folate metabolism genetic variants modify the association between prenatal PFAS exposure and birth outcomes. Methods We analyzed data from 338 mother-infant pairs in the Taiwan Birth Panel Study. Cord blood concentrations of four PFAS were measured using ultra-performance liquid chromatography–tandem mass spectrometry. Infant genotypes were assessed with the Taiwan Biobank Array, and we focused on three previously identified single nucleotide polymorphisms (SNPs) related to birth outcomes and five SNPs related to folate metabolism. Gene-environment interactions were evaluated using generalized linear regression and two mixture models (quantile g-computation and Bayesian kernel machine regression). Results Prenatal PFOS, PFUA, and PFAS mixture exposure were associated with lower birth weight, and associations between PFAS and birth weight and head circumference varied by genetic variants. We found interaction between PFNA exposure and MTNR1B rs10830963, a birth weight-related SNP. Also, MTR rs1805087 AG/GG carriers had greater PFOS and PFAS mixture-related birth weight reductions. Meanwhile, there were stronger evidence of PFAS mixture-birth weight associations in HMGA2 rs1351394 CC and rs1042725 TT carriers. Conclusion Genotypes associated with folate metabolism and birth size modified the associations between prenatal PFAS exposure on birth weight and head circumference.